rs763841075

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBS1_Supporting

The NM_002087.4(GRN):c.415T>C(p.Cys139Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,612,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GRN
NM_002087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000146 (214/1461708) while in subpopulation MID AF= 0.00416 (24/5768). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4_exome. There are 111 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4 linkuse as main transcript	c.415T>C	p.Cys139Arg	missense_variant	5/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8 linkuse as main transcript	c.415T>C	p.Cys139Arg	missense_variant	5/13	1	NM_002087.4	P1	P28799-1

Frequencies

GnomAD3 genomes

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251476

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000146

AC:

214

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73754

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 139 of the GRN protein (p.Cys139Arg). This variant is present in population databases (rs763841075, gnomAD 0.04%). This missense change has been observed in individual(s) with frontotemporal dementia or Alzheimer disease (PMID: 21800185, 23724906, 24503614, 27632209, 27997711, 34162492, 34435519). ClinVar contains an entry for this variant (Variation ID: 589965). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GRN function (PMID: 20028451, 22781549, 26652843). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	Reported previously in association with a wide spectrum of later-onset ALS-FTLD neurological phenotypes (Brouwers et al., 2008; Piaceri et al., 2014; Redaelli et al., 2018); Asymptomatic carriers of this variant have been found to have lower serum/plasma PGRN levels compared to controls but not as low as in cases with null variants, suggesting a partial loss of function (Sleegers et al., 2009; Finch et al., 2009; Guven et al., 2019); Published functional studies demonstrate that this variant leads to reduced neurite outgrowth stimulating activity compared to wild type (Wang et al., 2010); This variant is associated with the following publications: (PMID: 32772750, 24503614, 27997711, 19158106, 19288468, 30475763, 18565828, 25352065, 23392204, 26444794, 18314228, 20020531, 23742080, 25575133, 26652843, 27632209, 23684369, 22647257, 20028451, 23724906, 21800185, 31031559) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2017

The p.C139R variant (also known as c.415T>C), located in coding exon 4 of the GRN gene, results from a T to C substitution at nucleotide position 415. The cysteine at codon 139 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been detected in several individuals with frontal lobe temporal dementia, progressive late onset dementia, and corticobasal syndrome (Brouwers N et al. Neurology, 2008 Aug;71:656-64; Finch N et al. Brain, 2009 Mar;132:583-91; Bernardi L et al. Neurobiol. Aging, 2009 Nov;30:1825-33; Gómez-Tortosa E et al. Eur. J. Neurol., 2013 Sep;20:1319-24; Bagnoli S et al. Cell. Mol. Neurobiol., 2012 Jan;32:13-6; Rodríguez-Rodríguez E et al. Parkinsonism Relat. Disord., 2013 Aug;19:768-9; Guven G et al. PLoS ONE, 2016 Sep;11:e0162592). In vitro functional studes have shown this variant is likely to impair the physiological processing of the protein and structural modeling predicts this variant has a destabilizing effect on the protein (Brouwers N et al. Neurology, 2008 Aug;71:656-64; Wang J et al. J. Neurochem., 2010 Mar;112:1305-15; Karch CM et al. Neurobiol. Aging, 2016 Feb;38:215.e1-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

GRN-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2023

The GRN c.415T>C variant is predicted to result in the amino acid substitution p.Cys139Arg. The c.415T>C variant has been reported in patients with various neurodegenerative conditions including Alzheimer disease, frontotemporal dementia, semantic dementia, progressive nonfluent aphasia, and corticobasal syndrome (Bernardi L et al. 2008. PubMed ID: 18314228; Bagnoli S et al. 2011. PubMed ID: 21800185; Antonell et al . 2012. PubMed ID: 22647257; Piaceri et al. 2014. PubMed ID: 24503614; Redaelli et al. 2017. PubMed ID: 27997711; Guven et al. 2016. PubMed ID: 27632209). In one report the c.415T>C variant detected in a patient with progressive nonfluent aphasia but also in two unaffected family members age 66 and 42 years of age (Antonell A et al. 2012. PubMed ID: 22647257). While mutant GRN protein levels did not differ from non-carrier family members, in an axonal outgrowth assay, the p.Cys139Arg mutated PGRNs did not stimulate neurite outgrowth (Wang J et al. 2009. PubMed ID: 20028451). The c.415T>C variant has also been reported in over 40 individuals in gnomAD and has been interpreted as uncertain by several other laboratories in ClinVar. At this time the clinical significance of this variant is uncertain. -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;T;.;T;T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T;T;T;T

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-11

D;.;.;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.94

MVP

1.0

MPC

1.2

ClinPred

0.99

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over